Evidence suggests that several diseases later in life of major public health concern have fetal origins. Recent research posits a critical role for endocrine disruption during pregnancy; however, our etiologic understanding is insufficient. We conducted a two-generation follow-up study using the Michigan fish eater cohort. Our investigations showed that maternal dichlorodiphenyldichloroethylene (DDE) exposure is associated with endocrine-related outcomes (ERO) in offspring. Endocrine-related outcomes (ERO) included reduced age at menarche, and increased adult weight and fecundity. These findings favor the hypothesis that endocrine disruption in utero may lead to enduring changes in gene expression (epigenetic effect), possibly resulting in development of diseases later in life. However, there are insufficient data to support this assumption. We will address this knowledge gap by using two existing, unique cohorts with halogenated organic compounds (HOC) exposure via consumption of fish from the Great Lakes. To determine the association between intrauterine halogenated organic compounds (HOCs) exposure, endocrine disruption, and endocrine-related health outcomes, we propose to conduct two complementary and innovative epidemiologic studies in mother-child pairs. With these two cohorts, we will investigate (1) the halogenated organic compound (HOC)-endocrine disruption and (2) the endocrine disruption-endocrine-related outcomes (ERO) association. The halogenated organic compound (HOC)-endocrine disruption relationship will be assessed in an ongoing cohort study of mother-infant pairs for which halogenated organic compounds (HOC) are being determined. Using this cohort, we will first collect four consecutive saliva samples from 160-180 pregnant women to determine whether maternal halogenated organic compounds (HOC) exposure alters the profile of estrogen and progesterone during pregnancy. Second, in placental samples (fetus), we will determine expression of genes regulating sex steroid hormones and the involvement of halogenated organic compounds (HOCs). The endocrine disruption-disease association will be assessed in a nested case-control approach. Expression of genes regulating these hormones will be determined in cases (endocrine-related outcomes (ERO) positive) and controls in a unique female offspring cohort of Michigan fish eaters (n=151) with known prenatal dichlorodiphenyldichloroethylene (DDE) and polychlorinated Biphenyl (PCB) exposure. This is the first human study to estimate the degree to which prenatal halogenated organic compounds (HOC) exposure alters hormone levels and to assess the degree to which gene expression in women with endocrine-related outcomes (ERO) might be related to prenatal halogenated organic compounds (HOC). By estimating second-generation effects, we will provide new risk assessments to direct health guidelines and environmental policy in the Great Lakes region. This work brings together a multidisciplinary research team with a record of collaboration and expertise in epidemiology, toxicology, and genetics.